Effects of thyroid hormone on the insulin receptor in rat liver membranes.

Although many studies have investigated the complex interrelationships between thyroid hormone levels and insulin-glucose secretion and action, there is at present a lack of information concerning the effects of various thyroid hormone levels on insulin receptors. In the present study, rat liver membranes were prepared from control, hyperthyroid [10 micrograms L-T4 (T4)/100 g BW for 14 days], and hypothyroid rats and the binding characteristics of [125I]iodoinsulin to these membranes were studied. In addition, serum T3, T4, glucose, and insulin levels were measured. The mean (+/- SD) serum T4 and T3 levels were higher (P less than 0.05) in the T4-injected rats than in the hypothyroid rats (T4, 9.1 +/- 0.6 vs. 1.7 +/- 0.4 microgram/dl; T3, 144 +/- 18 vs. 30 +/- 16 ng/dl). When compared to controls, glucose levels were higher in the hypothyroid rats (116 +/- 11 vs. 141 +/- 14 mg/dl; P less than 0.05) and were statistically unaltered in thyrotoxicosis. Plasma insulin levels were increased in hypothyroidism (6.5 +/- 0.8 vs. 10.8 +/- 2.9 microU/ml; P less than 0.05) and decreased in thyrotoxicosis (7.5 +/- 0.5 vs. 28.3 +/- 15 microU/ml; P less than 0.05). Despite these alterations, membrane binding and the derived Scatchard plots were not significantly different in the hyperthyroid or hypothyroid groups. In summary, the present studies indicate that plasma membrane insulin receptor number and affinity are unaltered regardless of the thyroid state of the rat.

Survival with oral d-sotalol in patients with left ventricular dysfunction after myocardial infarction: rationale, design, and methods (the SWORD trial).

Impaired left ventricular function after acute myocardial infarction (AMI) is associated with an increased risk of death. Despite recent advances in the management of these patients, sudden death accounts for up to 50% of this mortality, and effective treatment strategies have yet to be identified. Preliminary trials with amiodarone have offered promise that drugs that prolong action potential duration by blocking the potassium channel may be useful in reducing this mortality. The Survival With Oral d-Sotalol (SWORD) trial is a multicenter, multinational study which tests the hypothesis that the class III agent d-sotalol will reduce all-cause mortality in high-risk survivors of AMI. The trial will enroll 6,400 patients with left ventricular dysfunction (ejection fraction < or = 40%) and a recent (6 to 42 days) or a remote (> 42 days) AMI with overt heart failure (New York Heart Association class II or III). In approximately 500 centers throughout the world, men and women aged > or = 18 years will be enrolled and randomized to placebo or d-sotalol (200 mg/day). The minimal follow-up will be 18 months. The trial has a 90% power to detect a 20% reduction in all-cause mortality. The rationale, design, and trial methods are described.

Thyrotropin secretion in starved rats is enhanced by somatostatin antiserum.

Previous studies have demonstrated that serum TSH and GH decrease during fasting. Taking advantage of the fact that somatostatin antiserum administration is an effective, specific method of blocking endogenous somatostatin activity, we performed the present investigation to explore whether known fasting-induced increases in somatostatin might underlie the mechanism(s) of this decrement. After a 48 hour fast, two groups of male rats were anesthetized and an indwelling right atrial catheter inserted. The control rats (n = 11) were injected with normal sheep serum and the experimental rats (n = 9) were injected with a specific antiserum to cyclic somatostatin; one and one-half hours later, blood was collected in a basal state after which 200 ng TRH was injected. The basal mean (+/- SE) T3 and T4 concentrations were 23 +/- 3 ng/dl and 1.9 +/- 0.1 ug/dl, respectively, in the fasted control group and 30 +/- 2 ng/dl and 2.3 +/- 0.2 ug/dl in the fasted somatostatin antiserum injected rats. While serum T4 and T3 levels were statistically unchanged between these two groups, basal TSH increased from 537 +/- 81 ng/ml in the control rats to 2913 +/- 742 ng/ml in the somatostatin antiserum-treated rats (P less than 0.05). Basal growth hormone levels were also higher in the somatostatin antiserum-injected rats (196 +/- 19 ng/ml vs 72 +/- 7 ng/ml (P less than 0.0025). TSH peak values following TRH injection were not different in the two study groups. In summary, the present study indicates that: (1) somatostatin antiserum increases both basal GH and TSH values in fasting rats; and (2) somatostatin and TRH may act through different pathways to modulate TSH secretion. By implication, therefore, it is suggested that enhanced somatostatin-like activity may represent one mechanism mediating the fasting-induced decrement observed in serum TSH and GH.

Hemodynamic changes during induction of anesthesia with eltanolone and propofol in dogs.

The purpose of this study was to examine global and regional hemodynamic changes during induction of anesthesia with eltanolone, a new short-acting steroid hypnotic, as compared to propofol, in chronically instrumented dogs. The effects on cardiac performance were assessed in six animals. Renal and hepatic blood flows were examined in a separate study including five animals. Two doses of each drug were investigated: eltanolone 2.5 and 5 mg/kg and propofol 7.5 and 15 mg/kg. Left atrial filling pressures and cardiac output were not affected by either drug. Maximum rate of increase of left ventricular pressures decreased both with eltanolone (-28% and -40% from awake control for the 2.5 and 5 mg/kg doses, respectively) and with propofol (-19% and -30% from awake controls with 7.5 and 15 mg/kg respectively). In contrast to propofol, eltanolone preserved arterial blood pressure. Propofol lowered systemic vascular resistance (-21% and -39% with the low and high dose, respectively), and only slightly decreased left ventricular wall thickening fraction (-16% and -21%). Eltanolone did not affect systemic vascular resistance but reduced the wall-thickening fraction dose-dependently (-28% and -61%). Propofol, but not eltanolone, induced moderate coronary vasodilation. Hepatic arterial blood flow velocity decreased dose-dependently (-21% and -64%) during eltanolone anesthesia whereas, in contrast, it increased after propofol (+59% and +64%). Renal and portal venous blood flows remained essentially unaltered from awake conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Global and regional haemodynamic effects of urapidil in conscious dogs with chronic coronary artery occlusion.

The haemodynamic effects of urapidil, an alpha 1-antagonist with central serotoninergic properties, were studied in an experimental canine model of chronic ischaemic heart disease. Global and regional haemodynamic recordings were made in conscious dogs with ameroid-induced single vessel coronary artery occlusion. Three intravenous bolus-infusion doses of urapidil (0.1 mg kg-1 + 0.3 mg min-1; 0.5 mg kg-1 + 1.5 mg min-1; 2.5 mg kg-1 + 7.5 mg min-1) were given on separate occasions in 12 animals. Regional blood flows were measured with radioactively labelled tracer microspheres. The effects of urapidil and dipyridamole, a powerful arteriolar vasodilator, on regional myocardial blood flow distribution to normal and collateral-dependent myocardium were compared. Urapidil caused a dose-dependent reduction of arterial blood pressure. There was moderate tachycardia and decreased left atrial filling pressures at the higher doses. Urapidil was a much weaker coronary vasodilator than dipyridamole. Dipyridamole caused maldistribution of intercoronary and transmural flows (endo-to-epicardial flow ratio in collateral-dependent regions from 1.35 +/- 0.07 to 0.7 +/- 0.13 and flow ratio between collateral-dependent and normal regions from 1.09 +/- 0.03 to 0.57 +/- 0.14). Urapidil preserved blood flow to both regions. Urapidil did not affect systolic wall thickening fraction in normal or ischaemic regions of the heart. Renal (+16%) and splanchnic perfusion (+45%) increased during urapidil infusion. Urapidil preserves myocardial function and perfusion and increases renal and intestinal blood flow in dogs with chronically ischaemic hearts.

Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol.

BACKGROUND: Left ventricular dysfunction after myocardial infarction is associated with an increased risk of death. Other studies have suggested that a potassium-channel blocker might reduce this risk with minimal adverse effects. We investigated whether d-sotalol, a pure potassium-channel blocker with no clinically significant beta-blocking activity, could reduce all-cause mortality in these high-risk patients. METHODS: Patients with a left ventricular ejection fraction of 40% or less and either a recent (6-42 days) myocardial infarction or symptomatic heart failure with a remote (> 42 days) myocardial infarction were randomly assigned d-sotalol (100 mg increased to 200 mg twice daily, if tolerated) or matching placebo twice daily. FINDINGS: After 3121 of the planned 6400 patients had been recruited, the trial was stopped. Among 1549 patients assigned d-sotalol, there were 78 deaths (5.0%) compared with 48 deaths (3.1%) among the 1572 patients assigned placebo (relative risk 1.65 [95% CI 1.15-2.36], p = 0.006). Presumed arrhythmic deaths (relative risk 1.77 [1.15-2.74], p = 0.008) accounted for the increased mortality. The effect was greater in patients with a left ventricular ejection fraction of 31-40% than in those with lower (